The spread of anthrax spores via the mail system in the fall of 2001, followed by the death of several American citizens, demonstrated that bioterrorism is a highly relevant threat that can have great impact on people's health and sense of fear. Plague is among the most contagious and lethal bacterial diseases with potential for illegitimate use. Historically, plague has been implicated in large epidemics that were able to change entire societies. Today, smaller plague outbreaks are not uncommon in many countries, and the disease can still induce public panic. The latter is exemplified by the suspected outbreak of pneumonic plague in Surat, India in 1994, leading 600 000 people to flee the town (Perry et al., (1997) Clin Microbiol Rev 10:35).
The causative agent of plague was identified in 1894 as the Gram-negative bacteria Bacterium pestis, later called Yersinia pestis in honor of Alexandre Yersin (Perry et al., (1997) Clin Microbiol Rev 10:35). Among the species of the genus Yersinia, Y. pestis is most closely related to Y. pseudotuberculosis (Achtman et al., (1999) Proc Natl Acad Sci USA 96:14043). Y. pestis is one of history's greatest infectious killers, with the historic plague epidemics claiming as many as 200 million lives by some estimates (Perry et al., (1997) Clin Microbiol Rev 10:35). In the modern US, plague is endemic mainly in the southwestern states, with the most cases occurring in New Mexico. Worldwide, a few thousand cases of plague are reported every year, with a mortality rate usually at 5-10% (WHO (1999) Weekly Epidemiological Record 74:340).
Plague is a zoonotic disease; the bacteria spreads naturally via infected fleas in a rodent reservoir population. The reasons for the cyclic nature of plague epidemics are not defined. However, cycles within rodent populations are believed to play an important role. Once the flea has transferred the bacteria to its host, Y. pestis spreads to adjacent lymph nodes, where it rapidly multiplies, causing swollen and necrotic buboes to appear (Butler et al. (1995) In Principles and practice of Infectious Diseases p. 2070) The bacteria can also spread to the blood stream, causing septicemia, and in some cases, secondary pneumonic plague. Pneumonic plague can spread directly from person to person, is highly contagious, and almost 100% lethal when untreated (Ratsitorahina et al. (2000) Lancet 355:111). This is in contrast to bubonic plague, which has a lethality rate of 50-60%. The time from transmission to disease onset varies with the route of infection and the individual, but in general it is assumed an incubation period of 2-6 days for pneumonic plague and 1-7 days for bubonic plague.
Outbreaks of pneumonic plague are rare; the last known case where plague was spread from person to person in the US was 1924-25 (Perry et al., (1997) Clin Microbiol Rev 10:35). However, this might be a clinical course of plague were it to occur during a biological attack (Inglesby et al., (2000) Jama 283:2281). The use of an aerosolized bacteria will cause pneumonic infection. This estimated that 50 kg of Y. pestis spread with the wind towards a city of population 5 000 000, will cause 36 000 primary deaths and more than 100 000 deaths in total (WHO (1970) Health Aspects of Chemical and Biological Weapons, Geneva, p. 98). In addition, many people would attempt to flee the city, resulting in further spread of the disease. The establishment of the infection in the rodent population would lead to many subsequent cycles of disease in the area. The mentioned estimate of mortality is based upon treatment of the disease with appropriate antibiotics. Recent studies have reported the emergence of naturally occurring Y. pestis resistant to multiple antibiotics in Madagascar (Galimand et al., (1997) N Engl J Med 337:677; Guiyoule et al., (2001) Emerg Infect Dis 7:43). The natural spread of such strains, or the potential use of engineered antibiotic resistant strains in a attack, open the possibility of far more causalities. Therefore, it is of crucial importance to learn more about of the basic biology of Y. pestis, and how it interacts with the mammalian immune system. Through increased knowledge, new therapies against the disease can be developed.
Y. pestis harbors a very effective type III secretion system, called Ysc. This system allows attachment of the bacteria to the mammalian cell to occur, with the introduction of a channel from the bacterial and host cell cytoplasm. This allows translocation of protein effectors from the bacteria to the host cell cytosol. Many of these effectors act to suppress host cell signaling and phagocytosis (Cornelis et al., (2002) J Cell Biol 158:401; Cornelis et al., (2000) Proc Natl Acad Sci USA 97:8778). Most of the effector are called Yops, and are encoded by the 70 kD plasmid called pCD1 in the two strains for which the genomic sequence is known, KIM and CO92. For example, YopP/YopJ has the ability to strongly affect the signaling via the NF-κB and the MAP kinase pathways, both major inducers of inflammatory signals (Cornelis et al., (2002) J Cell Biol 158:401; Cornelis et al., (2000) Proc Natl Acad Sci USA 97:8778; Cornelis et al., (2000) Proc Natl Acad Sci USA 97:8778). YopH is a powerful phosphotyrosine phosphatase, and can also inhibit phagocytosis. Another potent member of this family is YopE, which has the ability to block signaling molecules via GTPase activating protein, affecting Rac,Rho and CdC42.
In spite of the designation of Y. pestis as a NIH/NIAID priority A pathogen, there are currently no licensed US vaccines against plague. A previous formalin-killed whole cell vaccine has been discontinued, and subunit vaccines containing V antigen and F1 capsule protein are still of an exploratory nature (Titball et al., (2004) Opin Biol Ther 4, 965-73). A live EV76-strain vaccine, which is avirulent due to a chromosomal deletion in the pgm locus (delta pgm), is still in use in the former Soviet Union. However, this vaccine may have side effects, and some vaccinated mice have died following inoculation (Titball et al., (2004) Opin Biol Ther 4, 965-73; Russell et al. (1995) Vaccine 13, 1551-6). One common problem with plague vaccines, in particular killed vaccines, has been the failure of these to induce protection against pneumonic plague, the disease form which would be expected following a bioterror attack (Titball et al., (2004) Opin Biol Ther 4, 965-73; Russell et al. (1995) Vaccine 13, 1551-6). Thus, there is a need for better vaccines to protect against both pneumonic and bubonic plague.